Individuals with schizophrenia have deficits in auditory sensory processing, evidenced by a reduced ability to discriminate pure tones. These deficits correlate with core negative symptoms of this illness such as impairments in detecting spoken emotional tone, in phonologic processing, and in reading attainment. Tone discrimination depends on excitatory connections amongst networks of layer 3 pyramidal cells in primary auditory cortex (AI). We have found evidence of impairments in these circuits in subjects with schizophrenia, including a 27% reduction in density of dendritic spines. Dendritic spine density reductions were correlated with reductions in density of intracortical, but not thalamocortical, excitory axon boutons in our preliminary studies,. Net reductions in dendritic spines can result from reduced spine emergence/persistence and/or increased spine retraction, driven by long-term potentiation (LTP) and long-term depression (LTD), respectively. The induction of LTP or LTD depends on the precise timing of excitation relative to cell action potential firing. We have found preliminary evidence of reductions in density of the local inhibitory inputs that control the temporal precision of pyramidal cell firing in layer 3 of AI, potentially shifting this balance. LTP-induced spine plasticity is mediated by a kalirin-7 dependent pathway while LTD-induced spine plasticity is mediated by spinophilin and its downstream effectors. Altered mRNA and/or protein expression of several of these pathway components have now been reported in schizophrenia. This includes our preliminary evidence for upregulated expression of spinophilin protein per dendritic spine in layer 3 of AI, which was correlated with the spine density reductions in this layer. Based on the above findings, we hypothesize that impaired auditory processing in subjects with schizophrenia reflects reductions in the intracortical, but not thalamocortical, excitatory circuits in layer 3 of AI. We have developed a model in which these reductions arise due to shifts in the balance of LTP- and LTD- induced spine plasticity resulting in a net enhancement of spine elimination within intracortical circuits. This balance may be shifted due to effects of impaired layer 3 inhibitory circuits on spike timing and/or due to altered expression of plasticity mediators, although the selective reductions in intracortical circuits we propose are most likely to require the interaction of these effects. We will examine this model in an integrated set of studies that will specifically test the hypotheses that in layer 3 of AI of subjects with schizophrenia: reductions in excitatory intracortical circuits are present (Aim 1); numbers of inhibitory boutons are reduced (Aim 2); mediators of LTP-induced spine plasticity are reduced (Aim 3); mediators of LTD-induced spine plasticity are increased (Aim 4); and that similar alterations in expression of these mediators, induced in a cell culture model system, interact with activity-dependent stimuli to result in reduced spine number and size (Aim 5). These studies are strongly translational and can provide a basis for future interventions to enhance auditory function in this illness and to prevent synaptic loss in the early stages of disease. PUBLIC HEALTH RELEVANCE: Individuals with schizophrenia have impairments in the ability to process sound, which appear to underlie important functional symptoms of this illness, including identifying spoken emotion and reading performance. We propose to examine whether individuals with schizophrenia have impairments in the structures making up the brain circuits responsible for the impaired sound processing, and examine mechanisms that may lead to loss of these circuit structures. The proposed studies may provide a basis for future interventions to improve sound processing in individuals with this illness, and to prevent loss of sound circuit components during the early stages of disease.